Urinary Levels of IL-1β and GDNF in Preterm Neonates as Potential Biomarkers of Motor Development: A Prospective Study

Objectives. To evaluate the association between inflammatory biomarkers, neurotrophic factors, birth conditions, and the presence of motor development abnormalities in preterm neonates. Methods. Plasma and urinary levels of cytokines (IL-1β, IL-6, IL-10, TNF, and IL-12p70), chemokines (CXCL8/IL-8, CCL2/MCP-1, CCL5/RANTES, CXCL10/IP-10, and CXCL9/MIG), and neurotrophic factors (BDNF and GDNF) were evaluated in 40 preterm neonates born between 28 and 32 incomplete weeks of gestation, at four distinct time points: at birth (umbilical cord blood) (T0), at 48 (T1), at 72 hours (T2), and at 3 weeks after birth (T3). Biomarkers levels were compared between different time points and then associated with Test of Infant Motor Performance (TIMP) percentiles. Results. Maternal age, plasma, and urinary concentrations of inflammatory molecules and neurotrophic factors were significantly different between groups with normal versus lower than expected motor development. Higher levels of GDNF were found in the group with lower than expected motor development, while IL-1β and CXCL8/IL-8 values were higher in the group with typical motor development. Conclusion. Measurements of cytokines and neurotrophic factors in spot urine may be useful in the follow-up of motor development in preterm neonates.

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Hydrocephalus due to multiple ependymal malformations is caused by mutations in the MPDZ gene

Abstract

Congenital hydrocephalus is considered as either acquired due to haemorrhage, infection or neoplasia or as of developmental nature and is divided into two subgroups, communicating and obstructive. Congenital hydrocephalus is either syndromic or non-syndromic, and in the latter no cause is found in more than half of the patients. In patients with isolated hydrocephalus, L1CAM mutations represent the most common aetiology. More recently, a founder mutation has also been reported in the MPDZ gene in foetuses presenting massive hydrocephalus, but the neuropathology remains unknown. We describe here three novel homozygous null mutations in the MPDZ gene in foetuses whose post-mortem examination has revealed a homogeneous phenotype characterized by multiple ependymal malformations along the aqueduct of Sylvius, the third and fourth ventricles as well as the central canal of the medulla, consisting in multifocal rosettes with immature cell accumulation in the vicinity of ependymal lining early detached from the ventricular zone. MPDZ also named MUPP1 is an essential component of tight junctions which are expressed from early brain development in the choroid plexuses and ependyma. Alterations in the formation of tight junctions within the ependyma very likely account for the lesions observed and highlight for the first time that primary multifocal ependymal malformations of the ventricular system is genetically determined in humans. Therefore, MPDZ sequencing should be performed when neuropathological examination reveals multifocal ependymal rosette formation within the aqueduct of Sylvius, of the third and fourth ventricles and of the central canal of the medulla.

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Mitophagy and Mitochondrial Quality Control Mechanisms in the Heart

Abstract

Purpose of Review

Mitochondrial homeostasis and quality control are essential to maintenance of cardiac function and a disruption of this pathway can lead to deleterious cardiac consequences.

Recent Findings

Mitochondrial quality control has been described as a major homeostatic mechanism in the cell. Recent studies highlighted that an impairment of mitochondrial quality control in different cell or mouse models is linked to cardiac dysfunction. Moreover, some conditions as aging, genetic mutations, or obesity have been associated with mitochondrial quality control alteration leading to an accumulation of damaged mitochondria responsible for increased production of reactive oxygen species, metabolic inflexibility, and inflammation, all of which can have sustained effects on cardiac cell function and even cell death.

Summary

In this review, we describe the major mechanisms of mitochondrial quality control, the factors that can impair mitochondrial quality control, and the consequences of disrupted mitochondrial quality control.

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Heterogeneity of Fibroblasts and Myofibroblasts in Pulmonary Fibrosis

Abstract

Purpose of Review

Idiopathic pulmonary fibrosis (IPF) is the most common form of interstitial lung disease of unknown etiopathogenesis with mean survival of 3–5 years and limited therapeutics. IPF is characterized by a loss of alveolar type II epithelial cells and aberrant activation of stromal cells, leading to a considerable effort to characterize the origin and activation mechanisms of fibroblasts and myofibroblasts in IPF lungs. In this review, the origin and contribution of fibroblast and myofibroblasts in lung fibrosis will be summarized.

Recent Findings

Lineage tracing experiments suggested that interstitial lung fibroblasts and lipofibroblasts, pericytes, and mesothelial cells differentiate into myofibroblasts. However, epithelial- and bone marrow-derived cells may give rise to collagen expressing cells but may not contribute to the pool of myofibroblasts.

Summary

There is great heterogeneity in fibroblasts and myofibroblasts in fibrotic lungs. Further, there is evidence for the expansion of pericyte-derived myofibroblasts and loss of lipofibroblasts and lipofibroblast-derived myofibroblasts in IPF.

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IJMS, Vol. 18, Pages 929: Molecular Ghrelin System in the Pancreatic Acinar Cells: The Role of the Polypeptide, Caerulein and Sensory Nerves

Ghrelin (GHRL) is an endogenous ligand for the growth hormone secretagogue receptor (GHS-R). Experimental studies showed that GHRL protects the stomach and pancreas against acute damage, but the effect of GHRL on pancreatic acinar cells was still undetermined. Aim: To investigate the effect of GHRL and caerulein on the functional ghrelin system in pancreatic acinar cells taking into account the role of sensory nerves (SN). Methods: Experiments were carried out on isolated pancreatic acinar cells and AR42J cells. Before acinar cells isolation, GHRL was administered intraperitoneally at a dose of 50 µg/kg to rats with intact SN or with capsaicin deactivation of SN (CDSN). After isolation, pancreatic acinar cells were incubated in caerulein-free or caerulein containing solution. AR42J cells were incubated under basal conditions and stimulated with caerulein, GHRL or a combination of the above. Results: Incubation of isolated acinar cells with caerulein inhibited GHS-R and GHRL expression at the level of mRNA and protein in those cells. Either in rats with intact SN or with CDSN, administration of GHRL before isolation of acinar cells increased expression of GHRL and GHS-R in those cells and reversed the caerulein-induced reduction in expression of those parameters. Similar upregulation of GHS-R and GHRL was observed after administration of GHRL in AR42J cells. Conclusions: GHRL stimulates its own expression and expression of its receptor in isolated pancreatic acinar cells and AR42J cells on the positive feedback pathway. This mechanism seems to participate in the pancreatoprotective effect of GHRL in the course of acute pancreatitis.

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#ELCC17 latest: men in need of more frequent lung screening than women @myESMO https://t.co/0bilAYllQG

#ELCC17 latest: men in need of more frequent lung screening than women @myESMO https://t.co/0bilAYllQG

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Comprehensive Transcriptome and Mutational Profiling of Endemic Burkitt Lymphoma Reveals EBV Type-Specific Differences

Endemic Burkitt lymphoma (eBL) is the most common pediatric cancer in malaria-endemic equatorial Africa and nearly always contains Epstein–Barr virus (EBV), unlike sporadic Burkitt lymphoma (sBL) that occurs with a lower incidence in developed countries. Given these differences and the variable clinical presentation and outcomes, we sought to further understand pathogenesis by investigating transcriptomes using RNA sequencing (RNAseq) from multiple primary eBL tumors compared with sBL tumors. Within eBL tumors, minimal expression differences were found based on: anatomical presentation site, in-hospital survival rates, and EBV genome type, suggesting that eBL tumors are homogeneous without marked subtypes. The outstanding difference detected using surrogate variable analysis was the significantly decreased expression of key genes in the immunoproteasome complex (PSMB9/β1i, PSMB10/β2i, PSMB8/β5i, and PSME2/PA28β) in eBL tumors carrying type 2 EBV compared with type 1 EBV. Second, in comparison with previously published pediatric sBL specimens, the majority of the expression and pathway differences was related to the PTEN/PI3K/mTOR signaling pathway and was correlated most strongly with EBV status rather than geographic designation. Third, common mutations were observed significantly less frequently in eBL tumors harboring EBV type 1, with mutation frequencies similar between tumors with EBV type 2 and without EBV. In addition to the previously reported genes, a set of new genes mutated in BL, including TFAP4, MSH6, PRRC2C, BCL7A, FOXO1, PLCG2, PRKDC, RAD50, and RPRD2, were identified. Overall, these data establish that EBV, particularly EBV type 1, supports BL oncogenesis, alleviating the need for certain driver mutations in the human genome.

Implications: Genomic and mutational analyses of Burkitt lymphoma tumors identify key differences based on viral content and clinical outcomes suggesting new avenues for the development of prognostic molecular biomarkers and therapeutic interventions. Mol Cancer Res; 15(5); 563–76. ©2017 AACR.

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